The host defense response is critically linked to induction of vascular adhesion molecules and chemoattractants which recruit leukocytes to pertinent inflammatory sites. Leukocyte migration to tissues is tightly regulated in order to ensure optimal delivery of microbicidal products. This process begins with tethering and rolling of leukocytes on the endothelial lining at the target tissue, followed by activation of integrins and firm adhesion to the vessel wall, culminating in transendothelial migration. The initial shear-resistant adherence of leukocytes to the endothelial surface is mediated by selectin receptor/ligand interactions. The selectin family consists of “leukocyte-specific” L-selectin and “vascular selectins” P- and E-selectin, each of which binds sialofucosylated determinants, prototypically displayed as sialyl Lewis x (sLex). On human hematopoietic cells, two glycoproteins decorated with sialofucosylated glycans and recognized by mAb HECA-452 have been characterized as major counter-receptors for the vascular selectins: a glycoform of P-selectin glycoprotein ligand-1 (PSGL-1) called Cutaneous Lymphocyte Antigen (CLA) and a glycoform of CD44 known as Hematopoietic Cell E-/L-selectin Ligand (HCELL).
Activated leukocytes entering an inflammatory site employ various cytotoxic mechanisms including generation of reactive oxygen species (ROS). Phagocytosis induces a respiratory burst accompanied by creation of superoxide anion (O2−) and hydrogen peroxide (H2O2). The lysosomal enzyme myeloperoxidase (MPO) then uses hydrogen peroxide together with halide electron donors (Cl−, I−) to synthesize toxic and more efficient ROS like hypohalous acids (HClO, HIO). It is thought that extracellular leakage/release of toxic oxidants damages surrounding tissue, including endothelium, resulting in vascular inflammatory conditions such as leukocytoclastic vasculitis, systemic vasculitis syndromes, and atherosclerosis.
Granulocyte colony-stimulating factor (G-CSF or GCSF) is a hematopoietic cytokine that stimulates leukocyte production and activation. G-CSF serves a key role in host defense, and its expression is markedly upregulated in response to inflammatory insults. G-CSF is commonly used therapeutically to stimulate myelopoiesis after chemo- and/or radiotherapy and to mobilize progenitor cells for hematopoietic stem cell transplantation (HSCT). Though generally safe, use of this cytokine can be associated with significant vascular complications, including angina pectoris and myocardial infarct, sickle cell vaso-occlusion, splenic rupture, and leukocytoclastic vasculitis. Indeed, cutaneous leukocytoclastic vasculitis has been observed in as many as 6% of patients receiving G-CSF, and G-CSF administration is known to induce flares of systemic vasculitis and localized vasculitis (e.g., uveitis).
Following G-CSF administration for mobilization of hematopoietic stem cells, circulating myeloid cells exhibit increased adhesive interactions with cytokine-stimulated vascular endothelium when compared to native leukocytes (NL). These G-CSF-mobilized leukocytes (ML) display increased E-selectin ligand activity resulting from G-CSF-induced expression of Golgi glycosyltransferases which control synthesis of sLex. Conspicuously, G-CSF induces expression of a novel E-selectin ligand, a glycoprotein with electrophoretic mobility of ˜65 kDa.
There is increasing evidence of vascular complications, including angina pectoris, myocardial infarct, and early restenosis of vascular stents, associated with clinical G-CSF administration. G-CSF has gained wide therapeutic use for hastening recovery of neutropenia induced by radiotherapy and/or chemotherapy, in treatment of cyclic neutropenia, and for mobilization of bone marrow progenitors for hematopoietic stem cell transplantation. Moreover, this agent is being considered for treatment of non-hematologic indications, including immunomodulation and neuroprotection. Accordingly, there remains a need to critically examine and prevent the negative effect(s) of G-CSF administration on vascular/tissue integrity, while retaining intended salutary effect(s). More generally, there is a need to identify molecular effectors of vascular/tissue injury that accompany release of myeloid cells from the marrow, and to therapeutically prevent these vasculopathic and organopathic effects.
Throughout this description, including the foregoing description of related art, any and all publicly available documents described herein, including any and all U.S. patents, are specifically incorporated by reference herein in their entirety. The foregoing description of related art is not intended in any way as an admission that any of the documents described therein, including pending United States patent applications, are prior art to embodiments of the present disclosure. Moreover, the description herein of any disadvantages associated with the described products, methods, and/or apparatus, is not intended to limit the disclosed embodiments. Indeed, embodiments of the present disclosure may include certain features of the described products, methods, and/or apparatus without suffering from their described disadvantages.